. 2020 Jul 21;21(14):5164. doi: 10.3390/ijms21145164

Table 2.

Clinical small molecule inhibitors of cellular receptors adaptor protein in NF-kB pathway.

Drug	Originator/Developer	Stage	Indication	Trail No.	Other Information
*Bruton’s tyrosine kinase (BTK) inhibitors*
Zanubrutinib	BeiGene	Launched at 2019	MCL	NCT04002297	BRUKINSA oral dose is 160 mg twice daily or 320 mg once daily. TEAE: Decreased neutrophil count, platelet count and hemoglobin [53]. Case reports of Hepatitis-B reactivation.
		Preregistration	CLL	NCT03734016
		Phase 3	BCL, RRWM	NCT03332173
		Phase 2	DLBCL, Follicular lymphoma, Lymphoma, CLL, Lymphosarcoma, FL, MZL	NCT03145064; NCT04282018
Acalabrutinib	AstraZeneca/Parexel	Phase 3	CLL	NCT04008706	Potentially serious TEAE: Severe bone marrow suppression, infections, bleeding, tumor lysis syndrome, and renal toxicity [61]. Report of Atrial-flutter in an off-label use. Herpes zoster infection and a case of Hepatitis-B reactivation observed.
	Acerta Pharma/AstraZeneca, Biologics Inc, Merck	Launched 2017	MCL	NCT02972840
	Acerta Pharma	Phase 3	CLL	NCT02970318
	Acerta Pharma/AstraZeneca	Phase 2	COVID-19	NCT04346199, NCT04380688
	Acerta Pharma/AstraZeneca	Phase 2	Chronic GVHD	NCT04198922
	Acerta Pharma	Phase 2	WM	NCT02180724
		Phase 2	Metastatic Pancreatic Cancer	NCT02570711
		Phase 2	RA	NCT02387762
	Acerta Pharma BV Merck Sharp & Dohme Corp.	Phase 2	Ovarian Cancer	NCT02537444
		Phase 2	NSCLC	NCT02448303
		Phase 2	Squamous Cell Carcinoma of the Head and Neck	NCT02454179
	Acerta Pharma/Swedish Medical centre	Phase 2	DLBCL	NCT03736616
Ibrutinib	Janssen/Pharmacyclics; M.D. Anderson Cancer Center	Launched 2013	CLL	NCT02801578	420 mg orally once daily dose for CLL. Serious TEAE: hemorrhage, hypertension, ventricular arrhythmias, atrial fibrillation, atrial flutter, decrease in blood cell counts and Tumor lysis syndrome. Invasive fungal infections and Hepatitis-B reactivation observed. Ibrutinib-induced autoimmune hemolytic anemia and rare nail plate abnormalities also seen [62].
		Launched 2013	WM	NCT02165397
		Launched 2013	MCL	NCT01646021
		Phase 2	GVHD	NCT02195869
	Janssen/Pharmacyclics	Phase 3	Metastatic Pancreatic Adenocarcinoma	NCT02436668
		Phase 3	DLBCL	NCT01855750
		Phase 3	RRCLL, SLL	NCT01578707
Dasatinib	BMS/Dana-Farber Cancer Institute	Launched 2006	CML, acute cell lymphoblastic leukemia-lymphoma	NCT00123487, NCT03020030	TEAE: Cytopenias, fluid retention, pleural effusion, dyspnea, gastrointestinal disorders, skin rash, headache and fatigue [63]. Low blood cell count, Pulmonary Arterial Hypertension and Tumor lysis syndrome also seen. Often requires dose interruption and/or dose reduction.
	BMS	Phase 3	Prostatic Neoplasms	NCT00744497
	BMS/NCI	Phase 2	DLBCL	NCT00608361
	BMS/NCI	Phase 2	Rhabdomyosarcoma	NCT0304170
	BMS/OSI pharma/M.D. Anderson Cancer Center	Phase 2	NSCLC	NCT00826449
	BMS/Massachusetts General Hospital	Phase 2	CLL	NCT00438854
	BMS/Massachusetts General Hospital	Phase 2	Cholangiocarcinoma	NCT02428855
	BMS	Phase 2	Breast Cancer	NCT00767520
	BMS/Jorge J. Castillo, MD	Phase 2	WM	NCT04115059
Tirabrutinib	Ono Pharmaceutical/Gilead Sciences	Registered	Lymphoma	NCT03162536	TEAE: neutropenia, lymphopenia, leukopenia, and erythema multiforme [64]. Also observed pneumocystis jirovecii pneumonia and interstitial lung disease in a patient at highest dose of 480 mg QD.
Tirabrutinib	Ono Pharmaceutical/Gilead Sciences	Preregistration	WM	NCT03740529
Rilzabrutinib	Principia Biopharma	Phase 3	Pemphigus vulgaris	NCT02704429	Orphan drug status for Pemphigus vulgaris and Idiopathic thrombocytopenic purpura.
Evobrutinib	Merck Serono/EMD Serono	Phase 3	MS	NCT04032158	TEAE: Nasopharyngitis and increases in levels of alanine aminotransferase, aspartate aminotransferase and lipase [65].
Evobrutinib	Merck Serono/EMD Serono	Phase 2	RA	NCT02784106
Orelabrutinib	InnoCare Pharma/Beijing	Phase 2	SLE		TEAE: thrombocytopenia and neutropenia [66]. Profile better than Ibrutinib.
Orelabrutinib	InnoCare Pharma/Beijing	Phase 2	MZL
ABBV-105	AbbVie	Phase 2	SLE	NCT03978520	Focus is on ABBV-599 which is the ABBV-105/upadacitinib-combination
ABBV-105	AbbVie	Phase 2	RA	NCT03682705
ABBV-599	AbbVie	Phase 2	RA, SLE	NCT03682705, NCT03978520
SAR-442168	Principia Biopharma/Sanofi	Phase 2	Relapsing MS	NCT03996291	Common TEAE: Headache, upper respiratory tract infection and nasopharyngitis [67].
Branebrutinib	BMS	Phase 2	RA, SLE, Sjogren’s syndrome	NCT04186871	In phase 1, no serious TEAE observed [68].
TAS-5315	Taiho Pharmaceutical	Phase 2	RA	NCT03605251	Observed decrease in platelet aggregation and prolonged bleeding time in phase 1 [69].
Remibrutinib	Novartis	Phase 2	Asthma, Sjogren’s syndrome, Urticaria	NCT03944707, NCT04035668, NCT04109313	Phase 2 trial in Urticaria suspended due to COVID-19.
BMS-986142	BMS	Phase 2	RA	NCT02638948	TEAE: dizziness and nausea. Increase in Alanine aminotransferase [70].
BMS-986142	BMS	Phase 2	Sjogren’s syndrome	NCT02843659
Fenebrutinib	Genentech	Phase 2	Urticaria	NCT03693625	Higher doses may increase liver enzymes [71].
Poseltinib	Hanmi Pharmaceutical/Eli Lilly	Phase 2	RA	NCT02628028	Phase 2 discontinued as study failed to demonstrate its target effectiveness in the interim results [72].
Spebrutinib	Celegene	Phase 2	RA	NCT01975610	Celgene acquired by Bristol-Myers Squibb.
Spebrutinib	Celegene	Phase 1	CLL	NCT01732861	Celgene acquired by Bristol-Myers Squibb.
DTRMWXHS-12	Zhejiang DTRM Biopharma	Phase 2	DLBCL, R and RCLL, Follicular Lymphoma	NCT04305444	No development reported for B-cell lymphoma.
		Phase 1	MCL	NCT03836768	No development reported for B-cell lymphoma.
		Phase 1	CLL, BCL	NCT02891590	Evaluate the safety, tolerability and PK profile.
CT-1530	Centaurus Biopharma Co., Ltd.	Phase 1/2	B Cell-NHL, CLL, WM	NCT02981745	Discontinued for all indications
REDX08608	Redx Pharma/Loxo oncology	Phase 1/2	CLL/SLL or NHL	NCT03740529	In basal cell cancer, no development reported.
M-7583	EMD Serono	Phase 1/2	MCL, DLBCL, Relapsed/Refractory B Cell Malignancies	NCT02825836	TEAE: Neutropenia, febrile neutropenia and pneumonia [73].
ARQ-531	ArQule/Merck	Phase 1/2	Hematological malignancies	NCT03162536	Well-tolerated through 65 mg QD [74].
Vecabrutinib	Biogen Idec, Sunesis Pharmaceuticals	Phase 1/2	Hematological malignancies	NCT03037645	TEAE: Anemia, headache and night sweats.
TAK-020	Takeda	Phase 1	RA	NCT02413255	TEAE; Abdominal distension, upper abdominal pain, nausea, and headache
BIIB068	Biogen	Phase 1	SLE	NCT02829541	No update beyond phase 1
AC-0058TA	ACEA Biosciences	Phase 1	SLE	NCT03878303	Phase 1 for Autoimmune disorders completed in 2017 and no further progress reported.
SN-1011	Sinomab	Phase 1	Autoimmune disorder	NCT04041544
BIIB-091	Biogen	Phase 1	Healthy Volunteer (MS)	NCT03943056	Completes phase 1 trial for Multiple sclerosis.
TG-1701	Eternity Bioscience/TG Therapeutics	Phase 1	Healthy Volunteer (NHL, CLL)	NCT04291846	Encouraging safety profile.
CG-806	CrystalGenomics, Aptose Biosciences	Phase 1	CLL, SLL, NHL	NCT03893682	No drug-related dose-limiting toxicities.
*Interleukin-1 receptor-associated kinase (IRAK) inhibitors*
PF-06650833	Pfizer	Phase 2	RA	NCT02996500	TEAE: Infections and infestations [75].
CA-4948	Curis Pharmaceuticals	Phase 1	AML, MDS	NCT04278768	Adverse events: amylase/lipase increased neutrophil count decreased, rash and rhabdomyolysis [76].
CA-4948	Curis Pharmaceuticals	Phase 1	Hematological malignancies	NCT03328078
R-835	Rigel Pharmaceuticals	Phase 1	Autoimmune and Inflammatory Diseases		Rigel initiates phase 1 clinical trial [77].
BAY-1834845	Bayer	Phase 1	Pelvic Inflammatory Disease	NCT03054402	No update beyond phase 1 for Pelvic Inflammatory Disease
			Inflammation	NCT03244462
			Psoriasis	NCT03493269
BAY-1830839	Bayer	Phase 1	RA	NCT03540615
BAY-1830839	Bayer	Phase 1	Health volunteers (For RA)	NCT03965728
*Cellular Inhibitor of Apoptosis Proteins (c-IAP) inhibitors*
Birinapant (TL32711)	Jonsson Comprehensive Cancer Center, NCI	Phase 2	High Grade Ovarian, Fallopian Tube, Primary Peritoneal Cancer	NCT02756130	Birinapant and pembrolizumab combination had futile outcome in patients with MSS colorectal cancer [78].
Birinapant (TL32711)	TetraLogic Pharmaceuticals	Phase 1	Hepatitis B	NCT02288208
APG-1387 (SM-1387)	Ascentage Pharma	Phase 2	Advanced Solid Tumors	NCT04284488	TEAE: Elevated bilirubin, lipase increase and shortness of breath [79]. Exploring for Hepatitis B in both Treatment-experienced and naïve patient.
		Phase 2	Myelofibrosis	NCT04354727
		Phase 1	Advanced Solid Tumors or Hematologic Malignancies	NCT03386526
	Ascentage Pharma, HealthQuest Pharma	Phase 1	Chronic Hepatitis B	NCT03585322
LCL-161	Mayo Clinic	Phase 2	RR Plasma Cell Myeloma	NCT01955434	Hematologic toxicities: thrombocytopenia and anemia [80]. Completed phase I trial in multiple myeloma. No development reported for pancreatic cancer and solid tumors.
	MD Anderson Cancer Center, NCI, Novartis	Phase 2	Myelofibrosis	NCT02098161
	Novartis Pharmaceuticals	Phase 2	Breast Cancer	NCT01617668
	Novartis Pharmaceuticals	Phase 2	Small Cell Lung Cancer Ovarian Cancer	NCT02649673
	US Oncology Research Novartis, Delta Clinical Research, LLC	Phase 1	Metastatic Pancreatic Cancer	NCT01934634
	Novartis Pharmaceuticals	Phase 1	Neoplasms	NCT01968915
		Phase 1	Solid Tumors	NCT01240655
		Phase 1	Advanced Solid Tumors	NCT01098838
		Phase 1	MM	NCT03111992
ASTX660	Astex Pharmaceuticals	Phase 1	AML	NCT04155580	Common TEAE: Anemia, increased lipase and lymphopenia [81].
Debio 1143 (AT-406)	Debiopharm	Phase 1	Advanced Solid Tumors and Lymphomas	NCT01078649	TEAE: Mucositis, dysphagia and anemia [82].
CUDC-427	Curis Pharmaceuticals	Phase 1	Lymphoma	NCT01908413	Few patients discontinued and TEAE includes pruritus and fatigue [83].

Abbreviations: AML—acute myeloid leukemia; BCL—-B-cell leukemia; BMS—Bristol-Myers Squibb; CLL—chronic lymphocytic leukemia; CML—chronic myeloid leukemia; CMML—chronic myelomonocytic leukemia; DLBCL—diffuse large B-cell lymphoma; GVHD—graft versus host disease; HCC—hepatocellular Carcinoma; MCL—Mantle cell lymphoma; MDS—Myelodysplastic Syndrome; MM—Multiple myeloma; MS—multiple sclerosis; MZL—marginal zone lymphoma; NHL—Non-Hodgkin lymphoma; NSCLC—non-small cell lung cancer; RA—rheumatoid arthritis; RRCLL—relapsed and refractory chronic lymphocytic leukemia; RRMM—relapsed and refractory Multiple myeloma; SLL—small lymphocytic lymphoma; SLE—systemic lupus erythematosus; TCL—T-Cell Lymphoma; TEAE—Treatment-emergent adverse effects; WM—Waldenstrom macroglobulinemia.